JAK-STAT signaling in the therapeutic landscape of myeloproliferative neoplasms

Jennifer M O'Sullivan; Claire N Harrison

doi:10.1016/j.mce.2017.01.050

JAK-STAT signaling in the therapeutic landscape of myeloproliferative neoplasms

Mol Cell Endocrinol. 2017 Aug 15:451:71-79. doi: 10.1016/j.mce.2017.01.050. Epub 2017 Feb 3.

Authors

Jennifer M O'Sullivan¹, Claire N Harrison²

Affiliations

¹ Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, London, UK. Electronic address: jennifer.o'[email protected].
² Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, London, UK.

PMID: 28167129
DOI: 10.1016/j.mce.2017.01.050

Abstract

Myeloproliferative neoplasms (MPN) are a group of disorders defined by clonal proliferation of mature myeloid cells with overlapping clinical features. The driver mutations of these disorders, namely JAK2 (Janus Kinase), MPL (Myeloproliferative Leukaemia Virus) and CALR (Calreticulin) upregulate JAK-STAT signaling with increase in downstream transcription and gene expression. Epigenetic mutations are prevalent in MPNs but their interplay with aberrant JAK-STAT signaling is not known. This understanding lead to development of first targeted treatment in MPN; ruxolitinib for primary myelofibrosis. This has shown clinical benefit in overall survival and symptoms improvement but has yet to show significant disease modifying effects. This review will focus on contemporaneous understanding of altered JAK-STAT signaling in MPN and targeted treatments in clinical practice.

Keywords: JAK inhibitor; JAK-STAT; Myeloproliferative neoplasm; Primary myelofibrosis; Ruxolitinib.

Publication types

Review

MeSH terms

Antineoplastic Agents / therapeutic use*
Calreticulin / genetics
Calreticulin / metabolism
Cell Proliferation / drug effects
Cell Survival / drug effects
Gene Expression Regulation, Neoplastic*
Hematologic Neoplasms / drug therapy*
Hematologic Neoplasms / genetics
Hematologic Neoplasms / metabolism
Hematologic Neoplasms / pathology
Humans
Janus Kinase 2 / genetics*
Janus Kinase 2 / metabolism
Molecular Targeted Therapy
Myeloid Cells / drug effects
Myeloid Cells / metabolism
Myeloid Cells / pathology
Myeloproliferative Disorders / drug therapy*
Myeloproliferative Disorders / genetics
Myeloproliferative Disorders / metabolism
Myeloproliferative Disorders / pathology
Nitriles
Pyrazoles / therapeutic use*
Pyrimidines
Receptors, Thrombopoietin / genetics
Receptors, Thrombopoietin / metabolism
STAT Transcription Factors / genetics*
STAT Transcription Factors / metabolism
Signal Transduction

Substances

Antineoplastic Agents
CALR protein, human
Calreticulin
Nitriles
Pyrazoles
Pyrimidines
Receptors, Thrombopoietin
STAT Transcription Factors
MPL protein, human
ruxolitinib
JAK2 protein, human
Janus Kinase 2